Specific Consent Restrictions
Consent for the use of biospecimens in genetic research is tiered to (1) research related to heart disease, stroke, kidney diseases, other cardiovascular diseases, or risk factors associated with these diseases and (2) research related to any disease, health condition or risk factors. Use of biospecimens in non-genetic research is unrestricted.

Background

Many patients with heart failure have a normal or near-normal left ventricular ejection fraction (LVEF). Such patients share similar signs and symptoms as patients who have heart failure and a reduced LVEF, as well as an impaired quality of life and a poor prognosis. However at the time of TOPCAT, the benefit of medical therapies for heart failure was limited to those with a reduced LVEF. Due to a lack of favorable evidence from clinical trials, clinical guidelines offered no specific recommendations for the management of heart failure in patients with preserved LVEF except for attention to coexisting conditions.

Among patients with heart failure and a reduced LVEF and those with myocardial infarction complicated by heart failure and left ventricular dysfunction, mineralocorticoid receptor antagonists have been shown to be effective in reducing overall mortality and hospitalizations for heart failure. In small mechanistic studies involving patients with heart failure and preserved left ventricular function, mineralocorticoid receptor antagonists improved measures of diastolic function. However, rigorous testing was needed regarding their effect on clinical outcomes in patients with preserved LVEF. Therefore, the TOPCAT trial was initiated to determine whether treatment with spironolactone, an aldosterone antagonist, would improve clinical outcomes in patients with symptomatic heart failure and a relatively preserved LVEF.

Subjects

Patients 50 years of age or older were eligible if they had at least one sign and at least one symptom of heart failure on a pre-specified list of clinically defined signs and symptoms, a LVEF ≥ 45%, controlled systolic blood pressure (< 140 mm Hg or 140-160 mm Hg if subject was being treated with 3 or more medications), and a serum potassium level of less than 5.0 mmol per liter. In addition, eligible patients were stratified by two eligibility categories: (1) history of hospitalization within the previous 12 months, with management of heart failure a major component of the care provided, or (2) elevated brain natriuretic peptide (BNP) level within 60 days before randomization.

Exclusion criteria included severe systemic illness with a life expectancy of less than 3 years, severe renal dysfunction, and specific coexisting conditions, medications, or acute events.

A total of 3445 participants were enrolled, with 1722 assigned to the spironolactone group and 1723 assigned to the placebo group. Among these, 2464 participants were enrolled via the hospitalization stratum and 981 were enrolled via the BNP stratum.

Design

TOPCAT was a phase 3, multicenter, international, randomized, double-blind, and placebo controlled trial. Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio. Randomization was stratified according to whether the patient met the criterion for previous hospitalization or BNP elevation. The baseline visit included assessment of socio-demographics, physical characteristics, medical history, lifestyle factors, laboratory measures, electrocardiography variables and health-related quality of life and functional status.

Study drugs were initially administered at a dose of 15 mg once daily, which was increased as tolerated to a maximum of 45 mg daily during the first four months after randomization. Subsequent dose adjustments were made as required and subjects continued to receive other treatments for heart failure and co-existing illnesses. Measurement of potassium and creatinine levels was required within 1 week after a change in the study-drug dose and at each scheduled study visit. Follow-up visits to monitor symptoms, medications, and events and to dispense study drug were scheduled every four months during the subject’s first year on the study, and every six months thereafter. The mean follow-up interval was 3.3 years in each study group. Repository blood and urine samples were collected at the baseline and 1 year visits from consenting subjects.

The primary endpoint was a composite of cardiovascular mortality, aborted cardiac arrest or hospitalization for the management of heart failure. Secondary endpoints included all-cause mortality, hospitalization for heart failure management, new onset of diabetes mellitus or atrial fibrillation, and quality of life.

A subset of subjects also participated in the Echocardiography or Echocardiography and Vascular Stiffness ancillary studies. Echocardiography, and additionally tonometry in the Echocardiography and Vascular Stiffness study, were performed at baseline and at either 12 or 18 months following randomization. If the subject was already enrolled in the TOPCAT trial at the time the ancillary study was initiated, but had not yet reached the 18 month visit, baseline was determined via a retrospective analysis performed on any echocardiographic images completed within 60 days prior to TOPCAT enrollment and no tonometry was performed if applicable.

Conclusions

In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. However, the drug reduced the secondary endpoint of heart failure hospitalization incidence.

Please note that biospecimen availability is subject to review by the NHLBI, BioLINCC, and the NHLBI Biorepository. Certain biospecimens may not be made available for your request. Section 3 of the
BioLINCC handbook
describes the components of the review process

Visits (Vials):

04/24/2019

Serum

Plasma

Whole Blood

DNA

Buffy Coat

Urine

Total

Baseline

1,691

1,191

181

49

382

2,506

6,000

Month 4

3

1

0

0

1

3

8

Month 12

1,090

934

146

36

334

1,977

4,517

Visits (Subjects):

04/24/2019

Serum

Total number of subjects

Average volume (ml) per subject

Baseline

442

3.04

Month 4

1

3.70

Month 12

365

3.63

Plasma

Total number of subjects

Average volume (ml) per subject

Baseline

434

0.73

Month 4

1

2.30

Month 12

363

0.79

Whole Blood

Total number of subjects

Average volume (ml) per subject

Baseline

181

1.47

Month 12

146

1.52

Buffy Coat

Total number of subjects

Average vials per subject

Baseline

382

1.00

Month 4

1

1.00

Month 12

334

1.00

Urine

Total number of subjects

Average volume (ml) per subject

Baseline

436

8.25

Month 4

1

14.80

Month 12

351

8.14

DNA

Total number of subjects

Average mass (µg) per subject

Average vials per subject

Baseline

20

60.40

2.45

Month 12

15

27.09

2.40

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Materials Available

Study Documents

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